Transcript Nicotine - UCSD Cognitive Science

Nicotine/Tobacco
Tobacco Overview
• Leaves of Nicotiana tobacum
cured and (usually) smoked
• Indigenous to North America
• Smoked by natives for medicinal,
ceremonial purposes (~1 B.C.)
(enhancing fertility, predicting weather,
conducting war councils, enabling vision
quests, making peace)
Tobacco History
• Jean Nicot de Villemain introduces
tobacco to France, promotes
importation and cultivation (1556)
• Chewed recreationally, used for
ailments (e.g. headaches, colds) in
Europe (1500s)
• Tobacco becomes major cash crop of
American colonies, spurring demand
for slave labor (1600s)
Nicotine
• Nicotine is an alkaloid found naturally in tobacco
plants, tomatoes, potatoes, eggplant and green
peppers
• Nicotine isolated (1828)
Determinants of Tobacco Use
•
•
•
•
•
•
•
Socioeconomic status
Cultural characteristics
Biological elements
Stress
Advertising (for and against)
Price of tobacco products
Peer pressure
Estimated Numbers (in Millions) of Persons Aged 18
or Older Reporting Past Month Tobacco Use: 2000
Income/Education and Tobacco Use
Advertising
•
•
•
•
TV and Radio Ads illegal (1971)
Magazine Ads
Outdoor Ads
In-store promotions
– Tobacco accounts for 26.5% total sales of convenience stores
• Sponsorships
Targeted Advertising
• Exploit Ethnic Holidays
– Hispanic Heritage Month
– Black History Month
• Ethnic Groups
–
–
–
–
Rio / Dorado
American Spirit
Mild Seven
Uptown
• Children
– Joe Camel is cool
Hispanics
American Indians
Asians
African Americans
Death by Cigarette 1990-1994
Anti-Smoking Ad Campaigns
Scare tactics
Pharmacokinetics
• Readily absorbed from all over
the body, including
– Lungs (smoked)
– Mucosa (cigar, chewing
tobacco, gum, nasal spray)
– Skin (patch)
– Gastrointestinal tract
(uncommon)
Pharmacokinetics
• Absorption
– The most common way to get nicotine into your
bloodstream is through inhalation
– Your lungs are lined by millions of alveoli, which are
the tiny air sacs where gas exchange occurs
• These alveoli provide an enormous surface area, 90 times
greater than that of your skin, and thus provide ample access
for nicotine and other compounds
– Nicotine taken in by cigarette or cigar smoking takes
only 10-15 seconds to reach the brain but has a direct
effect on the body for only ~30 minutes
Pharmacokinetics
• Nicotine in smoke peaks in brain very rapidly, despite
relatively slow increase in blood concentration
• A typical cigarette contains 20 mg of nicotine
• ~2.5 mg of nicotine is absorbed
• Half-life: ~ 2 hours
• 80-90% metabolized in liver
Pharmacokinetics
• Metabolism & Elimination
– About 80 percent of
nicotine is broken down to
cotinine by enzymes in your
liver (e.g., CYP2A6)
– Nicotine is also metabolized
in your lungs to cotinine
and nicotine-N-oxide
– Cotinine and the remaining
nicotine is filtered from the
blood by your kidneys and
excreted in the urine
Smoking and MAO levels
Something in
cigarette smoke
seems to slow the
breakdown of
dopamine by
affecting MAO
levels
Pharmacodynamics
• Nicotine is a direct agonist
for nicotinic ACh receptors
• Nicotine initially causes a
rapid release of adrenaline,
the "fight-or-flight" hormone
Pharmacodynamics
• nAChRs found in limbic system (e.g. striatum, hippocampus,
accumbens), midbrain (e.g. VTA, substantia nigra), various
cortical areas (frontal lobe)
• nAChRs both postsynaptic and presynaptic, facilitating ACh,
DA, 5-HT and Glu action
• Nicotine also increases release of various neurohormones
• Has powerful effects on peripheral nervous system, heart, and
other organs
Acute Effects
• Classic stimulant effects of arousal (e.g. increased
heart rate and blood pressure, alertness, appetite
suppression)
• Carbon monoxide (in smoked form) reduces oxygen
transport to heart and other organs
• Vasoconstriction
• Can have calming (anxiolytic) effects in some
individuals
• Mild euphoria (relief?)
• Cognitive enhancements
• Antidepressant effects
Positive Effects
• Alzheimer's Disease
– The first neurons lost to Alzheimers are
cholinergic neurons
– Patients showed increased capacity for learning
verbal material when exposed to nicotine
• Symptoms reduced in
– ADHD
– Tourette's Syndrome
• Nicotine patches that slowly deliver nicotine were
used
• Glutamate
– Increases learning and memory
– Enhances connections between sets of neurons
Cognitive Enhancements?
• Working memory (e.g. N-back)
• Visual Perception (e.g. Critical Flicker Fusion)
• Visual Attention (e.g. reaction time)
• Motor function (e.g. reaction time)
• P300 (increased amplitude, decreased latency)??
Cognitive Enhancements
Enhanced primacy and recency effects
Effects on ERPs
deprived
smoking
nonsmoking
Chronic Effects: CANCER
• Tobacco use accounts for one-third of all
cancers
– Cancers relating to tobacco include:
•
•
•
•
•
•
Mouth
Pharynx
Larynx
Esophagus
Stomach
Lung
•
•
•
•
•
Cervix
Kidney
Bladder
Throat
Pancreas
• Cigarette smoking has been linked to about 90
percent of all lung cancer cases
• 430,000 annual deaths are attributed to
cigarette smoking
More Chronic Effects
•
•
•
•
•
•
•
Emphysema
•
Chronic bronchitis
Stroke
Vascular disease
Aneurysm
Esophageal reflux
Heart Disease
– It is estimated that nearly one-fifth of
deaths from heart disease are
attributable to smoking
*
Many of these are actually caused by
other chemicals in cigarette smoke or in
smokeless tobacco products
Secondary smoke also increases
the risk for many diseases
– Secondhand smoke is
estimated to cause
approximately 3,000 lung
cancer deaths per year among
nonsmokers and contributes to
as many as 40,000 deaths
related to cardiovascular
disease
– Exposure to tobacco smoke in
the home increases the severity
of asthma for children and is a
risk factor for new cases of
childhood asthma
– Environmental tobacco smoke
(ETS) exposure has been
linked also with sudden infant
death syndrome
Addiction
• Nicotine meets both the psychological and
physiological measures of addiction
– Psychological - People who are addicted to something
will use it compulsively, without regard for its negative
effects on their health or their life
– Physiological - anything that turns on the reward
pathway in the brain is addictive. Because stimulating
this neural circuitry makes you feel so good, you will
continue to do it again and again to get those feelings
back
Recent studies suggest those excitatory
amino acid systems and, in particular, Nmethyl-D-aspartate (NMDA) receptors,
may have an important role in this
phenomenon.
Drug Dependence Among Ever-Users
Tobacco
Heroin
Cocaine
Alcohol
Stimulants
Marihuana
0
10
20
% Dependent
30
40
Tolerance & Withdrawal
• Mild tolerance to behavioral and cardiovascular effects
• Upregulation of receptors has been interpreted as a
compensation to desensitization of nicotinic acetylcholine
receptors (nAChRs), and this prolonged desensitization has
been proposed as the mechanism of chronic tolerance to
nicotine
• Withdrawal may start after as little as one hour, may last for
as long as several months, can include:
–
–
–
–
–
Craving
Irritability
Anxiety
Dysphoria
Anger
–
–
–
–
–
Difficulty concentrating
Restlessness
Impatience
Increased appetite, weight gain
Insomnia
Treatment options
•
•
•
•
•
•
•
Behavior modification
Nicotine lozenges
Nicotine gum
Nicotine patches
Nicotine inhaler
Nicotine nasal spray
Bupropion SR
Challenges of Quitting
• Smokers seeking treatment for other drug
problems often find it harder to quit smoking
than other drugs
• Quitters often increase caffeine intake (blood
levels increased for up to 6 months) —
symptoms of nicotine withdrawal and caffeine
toxicity similar enough that reported withdrawal
symptoms may reflect mixture of the two
• Among self-quitters considered strongly
motivated to quit, 60-65% relapse in 1st month
after cessation
• Conditioned cues considered important elements
for maintenance and relapse
What’s new?
• Rimonabant (Acomplia; Zimulti)
– Cannabanoid Receptor (CB1) Antagonist
– Weight loss, tobacco cessation
– Phase III clinical trials
Acomplia was officially withdrawn by the European
Medicines Agency (EMEA) in January 2009 due to the
risks of dangerous psychological side effects, including
increased suicide risks.
– E-cigarettes
Cumulative Age of Initiation of Cigarette
Smoking*—United States, 1991
Advertising vs. Promotions
Advertising: newspaper, magazine,
outdoor, transit expenditures,
television and radio (before 1971).
Promotions: point-of-sale,
promotional allowances, sampling
distribution, direct mail, public
entertainment, endorsement, and
testimonial expenditures
Trends in daily smoking* among African American and white
high school seniors, by gender
Trends in Current* Cigarette Smoking by Grade in
School—United States, 1975-2001
Economics: Price and Tax
Cigarette = Dirty Needle?
• Nicotine is only 1 of ~ 4000 compounds released by
burning a cigarette
• Nicotine accounts for acute pharmacological effects
and for dependence, but...
• Adverse long-term cardiovascular, pulmonary, and
carcinogenic effects related to other compounds in
tobacco (esp. burned).
• If delivered more safely, nicotine may have potential
therapeutic value (e.g. Alzheimer’s disease).
or The Perfect Delivery Device?
• Rapid onset/offset of effects
• Additives facilitate nicotine effects, widen air passages, reduce
smoke visibility/odor
• Personal control of dosing
• Provides comforting habit/ritual
• Air vents and smoking style regulate amount delivered
Who Uses Tobacco: Ethnic Breakdown
Domestic vs. Foreign Use
Or not?
• Benefits = reversal of withdrawal?
• Highly variable dosing with smoking
• Inconsistent results when nonsmokers used as controls
(except for motor effects)
• Smokers generally have smaller P300 than ex-smokers and
never-smokers (Anokhin et al., 2000)
1.5
*
Mu Enhancement
1
0.5
0
nonsmokers
abstinent smokers
GROUP
smokers
2
nonsmokers
*
abstinent smokers
smokers
MU SUPPRESSION RATIO
1.5
1
0.5
0
ball
mimick
crayon
MOVEMENT TYPE
cigarette
self-move
Schizophrenia and Smoking
MU SUPPRESSION OVER SENSORIMOTOR CORTEX
FOR FIRST EPISODE PATIENTS vs CONTROLS
0.05
LOG [BASELINE/COND]
0
-0.05
CONTROLS
PATIENTS
-0.1
-0.15
-0.2
-0.25
HAND
CIGARETTE
SOCIAL
SMOKING
CONDITIONS
BIOMOTION
FUZZ
Treatments for Nicotine Dependence
• MAO inhibitors
• Noted that a constituent in cigarette smoke is an
MAO ( A and B) inhibitor- Fowler et al PNAS
(1996) and Fowler et al Nature (1996)
• Suggests that MAO inhibition may assist smokers
in quitting
Treatments for Nicotine Dependence
• Inhibition of nicotine metabolism
• Based on observations of differences in nicotine
metabolism ( CYP 2A6) and risk of dependence
formation – Pianezza et al Nature (1998)
• Clinical study with Methoxsalen ( CYP2A6
inhibitor ) reduced CO and smoking – Sellers et
al CPT (2000)